Major depressive illness represents one of the leading causes of disability with an estimated lifetime prevalence of 16.2% and an eventual suicide rate of from 6-15% (Blair-West, et al., Acta Psychiatr.Scand. (1997) 95:259-263; Inskip, et al., Br. J. Psychiatry (1998) 172:35-37) While numerous antidepressant drugs are currently available and are partially effective, most fail to produce remission in a significant fraction of patients. This lack of adequately efficacious antidepressants may be due to our present inadequate understanding of the underlying pathophysiology and neurobiology of major depression.
A number of new candidate drugs and procedures have been developed to overcome some of these difficulties. These include ketamine (Zarate, et al., Arch Gen Psychiatry 2006; 63: 856-864), 51-1T4 receptor agonists (Lucas, et al., Neuron, 2007; 55: 712-725), deep brain stimulation (Mayberg, et al., Neuron 2005; 45: 651-660, 2005), agomelatin (Kasper, et al., World J Biol Psychiatry 2009; 10: 117-126), and antagonists of CRF (Zoumakis, et al., Ann N Y Acad Sci 2006; 1083: 239-251), NK1 (Ebner, et al., Curr Pharm Des 2009; 15: 1647-1674), kappa opioid (Carr, et al., Neuropsychopharmacology 2010; 35: 752-763), and cholecystokinin (Smadja, et al., Psychopharmacology 1997; 132: 227-236) receptors. While some of these agents appear to have an increased speed of action and reduced side effect profile, they may not possess greater efficacy than existing drugs and may have further limitations themselves in terms of degree of invasiveness, losses of efficacy with chronic administration, and dissociative side effects. Moreover, while some of the newer agents can rapidly reverse the motoric (i.e., immobility) aspects of depression, most continue to have delayed actions on depressive anhedonia, one of the core symptoms of the illness (Friedman, et al., Neuropsychopharmacology 2009; 34: 1057-1066, Machado-Vieira, et al., Pharmacol Ther 2009; 123: 143-150).
Recently, however, the picture has begun to improve with significant advances in the elucidation of the basic neural circuitry of this disorder. In global terms, it now appears that depression arises from a shift of neural activity away from brain regions involved in motivation and behavioral performance towards regions involved in stress responses. (Mayberg, Biological Psychiatry 2007, 61: 729-730; Steciuk et al., Brain Research, 1999; 822: 256-259; Price et al., Neuropsychopharmacology, 2010, 35; 192-216 and Drevets, European Neuropsychopharmacology, 2009; 12:527-544; Stone et al., Neuroscience and Biobehavioral Reviews, 2008; 32:508-524). Thus, in both depressed patients and animal models of the disorder, brain structures controlling executive functions and behavioral performance such as the dorsolateral prefrontal motor and piriform cortex, lateral septal nucleus and nucleus accumbens tend to be deactivated or unresponsive to stimulation whereas areas controlling emotional and autonomic responses to stress including ventral limbic forebrain structures, amygdala, insula, bed nucleus of the stria terminalis, paraventricular nucleus of the hypothalamus and locus coeruleus tend to be overly activated or hyperresponsive.
The shift of activity between the motivational and stress regions has suggested that the heightened activity of the stress areas is the cause of the inhibition of the motivational regions.
Depression has a lifetime prevalence of approximately 17% with an economic burden of about $80 billion per year in our country. Currently available antidepressants are inadequate to meet this need because most have an unsatisfactory efficacy in a sizable fraction of patients and/or require several weeks to act, which can be especially deleterious for agitated, suicidal patients. It may, however, be possible to overcome these problems with the use of agents that immediately and selectively inhibit the brain's stress circuit via sensitive autoreceptors.
Various clinical neuroimaging and animal depression studies have shown that a key etiological factor in depression is the excessive activity of the central stress circuit, (Stone et al., 2008a) a group of brain nuclei that are highly sensitive to stress and that mediate the various autonomic, neuroendocrine, behavioral and aversive emotional responses to stressful stimuli. These findings therefore have suggested that it may be possible to initially treat depression rapidly and effectively by selectively targeting the central stress nuclei for acute inhibition, and that this method might help bridge the gap between the acute and chronic treatments of the illness.
Such a strategy was first employed by Weiss and colleagues (Simson et al., Neuropharmacology (1986) 25:385-389) and was directed at the locus coeruleus (LC), the main noradrenergic stress nucleus of the brain, which had been implicated in human depression (Bissette et al., Neuropsychopharmacology (2003) 28:1328-1335; Ordway et al., Biol. Psychiatry (2003) 53:315-323). Simson et al. studied rats who showed increased depressive-like immobility in a forced swim test as a result of previous exposure to traumatic electric shock stress. They found that infusion of the α2-adrenergic agonist, clonidine, in the LC to inhibit the latter's electrical activity, produced an immediate reduction of the depressive behavior consistent with the hypothesized role of the nucleus. Subsequently Stone et al provided further confirmatory evidence on the basis of experiments with another α-agonist, 6-fluoronorepinephrine, (6FNE), which produces an even more profound inhibition of the LC activity than clonidine as a result of the combined stimulation of inhibitory α1- and α2-receptors (Stone, et al., International Journal of Neuropsychopharmacology In press (2009); Stone, et al., Brain Res. (2009) 1291:21-31). This compound produced a more marked and rapid antidepressant response than clonidine when infused in the LC prior to several different behavioral tests. These findings have recently been confirmed by Stone et al in studies with dipivalyl-6-fluoronorepinephrine (dp6FNE), a catecholamine pro-drug that stimulates the 2 chief α-adrenergic inhibitory autoreceptors of the LC (Stone et al, Current Protocols in Neuroscience (2010) In press) This drug, at or below 1 mg/kg, i.p., h has been found to have immediate anti-immobility effects without motor stimulation or sedation in a model of chronic depression in mice (repeated forced swim) that is resistant to acute treatment with all other currently available antidepressants so far tested, including ketamine (FIG. 1) (Stone et al., Current Protocols in Neuroscience (2010) In press).
The mechanism by which excessive LC activity might lead to depression may involve the release of the inhibitory peptide galanin from noradrenergic fibers in the ventral tegmental area (Weiss, et al., Neuropeptides (2005) 39:281-287), thus inhibiting a key dopaminergic motivational behavioral system. Alternatively, it may involve excessive activation of postsynaptic α1-adrenoceptors by NE itself in certain forebrain regions, such as the prefrontal cortex, causing the neural activity in the latter structure to be markedly inhibited (Arnsten, et al., Biol. Psychiatry (2005) 57:1377-1384).
Central α1-adrenoceptors have long been known to play an essential role in behavioral activation under a variety of experimental conditions. Blockade of these receptors in a number of brain regions produces immobility in novel surroundings whereas stimulation may lead to behavioral activation in familiar environments (Stone et al., Neuroscience 1999; 94:1245-1252; Stone et al., Neuropharmacology 2001: 401: 354-261; Stone et al., Behav. Brain Res. 2004; 152:167-175). The LC appears to be a key region in this system in that it contains a dense concentration of al-receptor binding sites (Jones et al., J. Comp. Neurol., 1985; 231:190-208; Stone et al., Synapse, 2004, 54; 164-172) having the above behavioral properties (Stone et al., Behav. Brain Res. 2004; 152:167-175; Stone et al., Synapse, 2004; 54:164-172; Lin et al., Neuropsychopharmacology, 2007; 32:835-841). Moreover this nucleus is a site of convergence for systems regulating arousal (Cedarbaum, et al., J. Comp. Neurol. 1978; 178:1-16; Berridge et al., Psychol. Med. 1993; 23:557-564), motivated behavior (Aston-Jones; et al., Annu. Rev. Neurosci. 2005; 28:403-450; Bouret, et al., Trends Neurosci. 2005; 28:574-582), stress (Valentino, et al., Eur. J. Pharmacol. 2008; 583:194-203; Ma et al., Neuroscience 2008; 154:1639-1647; Korf et al., Neuropharmacology 1973, 12:933-938) and pain (Pertovaara, Prog. Neurobiol. 2006; 80:53-83) and can affect a wide range of behavioral and physiological functions.
While α1-adrenoceptors have traditionally been thought to mediate postsynaptic excitation (Hermann et al., J. Physiol. 2005; 562:553-568), several recent studies have shown that they can also depress excitatory synaptic or increase GABAergic neurotransmission in a number brain regions (McElligott, et al., Neuropsychopharmacology 2008; 33:2313-2323; Lei et al., J. Neurophysiol. 2007; 98:2868-2877). A reduced functional activity of the LC is known to lead to the activation of task-specific behaviors (Aston-Jones, et al., Annu. Rev. Neurosci. 2005; 28:403-450; Weiss et al., Neuropharmacology 1986; 25:367-384; Grant, et al., Biol. Psychiatry 2001; 49:117-129), while excessive LC activity has been shown to cause aversion and abandonment of rewarding behaviors (Smith et al., Brain Struct. Funct 2008, 213; 43-61; Taylor et al., Psychopharmacology 1988, 96; 121-134), and possibly depression (Grant et al., Biol. Psychiatry 2001, 49; 117-129; Simson et al., Neuropharmacology 1986; 25:385-389; Stone, Behavior and Brain Sciences 1982; 5:122). Determining how the functional activity of this nucleus is affected by α1-adrenergic stimulation that produces behavioral activation previously utilized local infusion of the selective α1-agonist, phenylephrine (PE), which produces a weak stimulation of exploratory behavior in rats (Stone et al., Synapse, 2004; 54:164-172). PE, however, is known to be only a partial agonist at brain α1-adrenoceptors (Johnson, et al., Eur. J. Pharmacol. 1986; 129:293-305; Law-Tho et al., Eur. J. Neurosci 1993; 5:1494-1500). In contrast, 6-fluoronorepinephrine (6FNE), which is the only known selective full agonist at all central α-adrenoceptors (Johnson et al., Eur. J. Pharmacol. 1986; 129; Brasili et al., Eur. J. Pharmacol. 1987; 144:141-146), produces extreme hyperactivity in the home cage when infused in the mouse LC.
Stimulation of α1-receptors of the locus coeruleus with the full agonist, 6FNE, produced a virtually complete cessation of the neural activity of this nucleus whereas blockade of these receptors with the α1-antagonist, terazosin, produced an excitation of virtually every neuron of the nucleus, as measured from the expression of c-Fos its cells (Stone, et al., International Journal of Neuropsychopharmacology In press (2009)). The activity of the LC was therefore shown to be reciprocally or inversely related to the level of ongoing motivated behavioral activity. Since depression is accompanied by an inhibition of many of these motivated behaviors and by a hyperactivity of the LC, it was reasoned that inhibition of the nucleus by the full agonist, 6FNE, would produce a potent antidepressant action. This was confirmed by tests of the effects of local infusion of 6FNE near the LC on 4 different tests of antidepressant activity: the acute forced swim, acute tail suspension, chronic open space forced swim and lipopolysaccharide induced anhedonia (Stone, et al., Brain Res. (2009) 1291: 21-31). From tests of anxiety in the open field and of the activity of stress-related brain regions after local infusion of 6FNE, these experiments also revealed that stimulation of these α-adrenergic receptors of the LC may act by inhibition of the organism's state of stress.
One of the drawbacks of current antidepressant agents is their slowness of action. Most presently available drugs require several weeks administration before they produce clinically significant antidepressant effects ((Sartorius et al., International Journal of Neuropsychopharmacology (2007) 10 Suppl 1: S1-207). This can be especially deleterious for agitated or suicidal patients who require immediate relief of symptoms and who may be resistant to psychotherapeutic or cognitive/behavioral-based interventions. It would be especially beneficial to address this problem with the use of drugs that selectively and rapidly inhibit central stress-sensitive brain areas known to be active during depression.